The insulin-like growth factor receptor (IGF-IR) is hyperactive and overexpressed in many breast cancers, and preclinical data have validated IGF-IR as a therapeutic target several IGF-IR inhibitors have recently entered clinical trials. We have shown that a new IGF-IR tyrosine kinase inhibitor (TKI) can reverse IGFIR-mediated transformation in vitro and block breast cancer xenograft growth in vivo. However, development of anti-IGF-IR TKIs has long been hindered by concerns about toxicity due to blockade of the highly similar insulin receptor (InsR). Indeed, all IGF-IR TKIs developed thus far show relatively equal potency against InsR. In contrast, monoclonal antibodies that specifically block IGF-IR, without crossreacting with InsR, have recently been developed, and many show preclinical activity. We are participating in a multi-institutional Phase 2 study of the anti-IGF-IR antibody CP-751,871 in combination with the aromatase inhibitor exemestane as first-line treatment in metastatic breast cancer. However, two critical questions remain regarding the targeting of IGF-IR. First, there are no validated biomarkers that predict response to anti-IGF-IR therapy. Second, it is not clear whether InsR, which can signal to many of the same pathways as IGF-IR, and can form IGF-IR/lnsR hybrid receptors, might need to be blocked. We hypothesize that biomarkers of IGF action identified in breast cancer cells will be modified in patient biopsies following treatment with the anti-IGF-IR-specific antibody CP-751,871, and may identify patients who will respond to IGF-IR targeted therapy. However, we predict that the greatest response may require targeting of both IGF-IR and InsR. To test our hypotheses we propose the following specific aims: 1) Identify biomarkers of IGF-IR activity in breast cancer cell lines, and then determine if these biomarkers are altered in patient biopsies from clinical trials of the new IGF-IR blocking antibody CP-751,871. 2) Determine the function of InsR and hybrid IGF-IR/lnsR in breast cancer cell lines, and whether targeting of both IGF-IR and InsR is more effective than targeting IGF-IR alone. 3) Test whether intermittent, rather than continuous, dosing of an IGF-IR/lnsR TKI (BMS-536924) is effective at inhibiting breast cancer growth, and determine combinations with other therapies that provide synergistic benefit. Our long term goal is to understand the role of IGF-IR in breast cancer, and thus advance the clinical development and implementation of IGF-IR inhibitors as effective therapies in breast cancer.